Hypercholesterolemia is related to an increased risk of heart diseases. A very effective way to reduce serum cholesterol levels is to inhibit the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is a main enzyme in the regulation of cholesterol biosynthesis. The HMG-CoA reductase inhibitors, commonly known as “statins”, act through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. Statins are useful in the treatment of hypercholesterolemia and associated diseases but are extremely susceptible to degradation at pH below 8. Statins at pH below 8 and particularly in acidic conditions, undergo elimination or isomerization or oxidation reactions to form conjugated unsaturated aromatic compounds, as well as the threo isomer, the corresponding lactones and other degradation products. Statins are particularly sensitive to an acidic environment (a low pH environment), in which hydroxyl acids are degraded into lactone. The tendency of HMG-CoA reductase inhibitors to degrade may be accelerated by possible interactions with other active ingredients or excipients present in the composition.
Fluvastatin sodium, is the [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt and Atorvastatin calcium, is the [R—(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. Fluvastatin and Atorvastatin are two statins particularly useful in therapeutics but prone to degradation reactions. The degradation of the active ingredient results in reduced effectiveness and treatment failure.
Furthermore, the stability of pharmaceutical compositions containing a HMG-CoA reductase inhibitor and in particular, Fluvastatin or Atorvastatin or salts thereof can also be influenced by the selection of the excipients.
Moreover, the poor flow properties of certain Statins may also generate difficulties when it has to be formulated in dosage forms suitable for oral administration, such as tablets, capsules, caplets, sachets or other solid dosage forms, thus limiting the choices of the excipients that can really be used.
Various methods are already known for the industrial preparation of oral dosage forms comprising a HMG-CoA reductase inhibitor e.g. Fluvstatin or Atorvastatin or salts thereof, as an active ingredient due to its useful therapeutical properties. However, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable stability due to the degradation of said active ingredient.
EP 0 547 000 discloses a stabilized pharmaceutical composition which comprises a statin and an alkaline stabilizing medium capable of imparting a pH of at least 8 to an aqueous solution or dispersion of the composition.
EP 1 148 872 discloses a stable solid pharmaceutical formulation comprising a statin and a buffering agent, such as a carbonate buffer or phosphate buffer, capable of adjusting the pH of the total formulation in the range from 6 to 9.
Furthermore, in EP 1 292 293 is disclosed a composition comprising a homogenous mixture of a statin with a buffering or basifying substance obtained by co-crystallization and/or co-precipitation of the statin and the buffering or basifying substance.
In addition, in long-lasting treatments such as hypercholesterolemia it is very important that the plasma concentration of the drug is constant. For this purpose, in order to attain and maintain constant levels of active ingredient in the plasma retard compositions are used from which the active ingredient is released into the biological system during several hours, typically more than 3 hours and less than 30 hours.
Several different types of formulations exist to obtain sustained release of a drug. In general sustained release can be obtained according to the following mechanisms:
i) Formulation of the drug in a swellable insoluble matrix. In this case, the gastrointestinal fluid penetrates the matrix, which swells, and the drug is dissolved and diffuses through the swelled matrix. The solubility and the dissolution rate of the drug, the swelling kinetics and the pores of the matrix are the key factors affecting the overall release rate.ii) Formulation of the drug in an eroding matrix basically consisting of soluble polymer. The drug release is controlled by the erosion rate and the swelling rate of the matrix. This system is not indicated for a highly soluble drug.iii) Diffusion control membrane systems. The membrane is consisted of insoluble but porous polymers and surrounds usually particles or cores containing the drug. Water penetrates the membrane, dissolves the drug, which comes out through the membrane pores. The number and size of the pores as well as the solubility of the drug are the most important factors for the overall release.iv) Osmotic system. A semi-permeable membrane with one or more orifice surrounds a core. The size of the orifice controls the release of the drug which is achieved via the osmosis phenomenon. This system requires special equipment and is considered expensive.
Fluvastatin's solubility in water (>50 g/l) does not allow the use of eroding matrix systems for a sustained release formulation, while an osmotic system would not be the preferred approach mainly for cost reasons. In swellable insoluble matrices the polymer hydrates and swells to form around the tablet a gellified layer that represents a diffusion barrier for the release of the drug. In this case and especially for highly soluble drugs an initial high drug release rate occurs (initial burst). Furthermore the release rate usually decreases depending on the square of time (˜t2).
Diffusion control systems, on the other hand, suffer from the well-known burst effect during the initial stage of drug release. Furthermore, they do not provide zero order release profile, which is the optimal for sustained release systems. Moreover, diffusion control systems require complicated manufacturing processes due to the additional steps for the coating application. Fluvastatin is a highly soluble drug so these phenomena occur at greater extend when the formulation is a classical matrix or diffusion control system.
EP 0 948 320 discloses a sustained release pharmaceutical composition comprising a water soluble salt of fluvastatin in a matrix formulation or diffusion-controlled membrane coated formulation.
Although each of the above patents represents an attempt to overcome the instability problems associated with pharmaceuticals compositions for immediate or sustained release comprising a HMG-CoA reductase inhibitor, there still exists a need for improving the stability and release rate of such pharmaceutical compositions without producing unwanted pharmaceutical effects and with low production costs.